Sciencemadness Discussion Board

Method for demethylation of secondary amine?

RabbitTy - 11-3-2021 at 23:11

Hi there!
Recently I have a question about the demethylation of Secondary amine. I have tried NIS(N-Iodosuccinimide, WO2017121648), didn't work out.
Doing some search, there are many ways to demethylate the tertiary amine,few for secondary amine.
appreciate any advice
structure Attached

Attachment: Structure.cdx (6kB)
This file has been downloaded 179 times

zed - 12-3-2021 at 16:25

Sorry. That file is in a format my Mac refuses to read.

CharlieA - 12-3-2021 at 17:25

Quote: Originally posted by zed  
Sorry. That file is in a format my Mac refuses to read.


Dr.Bob - 18-3-2021 at 12:06

What you have presented would make a fine PhD thesis project, not a quick question here. I have done demethylations on tert amines, which already is a big pain, and often very irreproachable but with a steroid with two secondary amines will be almost impossible to get a clean product. Good luck, but this will not be easy.

draculic acid69 - 20-3-2021 at 05:47

Alkyl/benzyl chloroformates work as well as creating an n-oxide and then reacting with iron sulfate might be possibilities

Dr.Bob - 20-3-2021 at 17:41

Do those methods work for secondary amines OK? I know ACE-chloride (alphachloroethyl chloroformate) is used for demethylating tertiary amines, but I did not think it worked well for secondary ones. Same for the N-oxide and iron sulfate ( a trace of water is helpful). I have seen both of those used, but the yields vary wildly, even for the same compound in the same conditions.

if you can use these or other conditions (eg, LiI in pyridine) and make it work, then congrats, as that is a tough problem. But you should plan for some serious time and effort to make it work. And then demand a degree for it.

HeYBrO - 20-3-2021 at 19:19

Quote: Originally posted by zed  
Sorry. That file is in a format my Mac refuses to read.

that is because it is a Chemdraw file. Here it is as a screenshot:

SM pic.png - 14kB

wxyz - 20-3-2021 at 19:51

Maybe you can make the amine temporarily tertiary by adding benzyl group, then remove the group you don't like, then remove the benzyl via H2 + Pd/C.

draculic acid69 - 20-3-2021 at 19:53

I realise now that I was thinking of a specific amine as a secondary amine that is actually a tertiary bad.thats all I know of n dealkylation

njl - 21-3-2021 at 07:34

I like wxyz's idea, seems like the elegant choice. Unfortunately you've got not only 2 secondary amines but also an alcohol so targeting one amine would be impractical.

clearly_not_atara - 21-3-2021 at 08:01

What you have asked for is not "demethylate a secondary amine" -- a difficult, but possible task -- but instead, "demethylate one secondary amine and not the other nearly identical secondary amine", which is something entirely different and almost impossible.

In any case, here is your reaction sequence:

1. Reaction with dibenzyl carbonate to the di-N-BOCylated compound.
2. Deprotonation with KH and cyclization of the upper-right NHMe and OH to a 1,3-oxazan-2-one by transesterification
3. Debenzylation of the remaining BOC group with Pd/C

That gives you a selective protection. Now:

4. N-chlorosuccinimide, base, low temperature -> N-chloroamine
5. Strong base (LDA? KH?) -> N-methyleneimine
6. Drop cold solution into warm mildly acidic water with rapid stirring -> hydrolysis
7. Further hydrolysis -> target compound

Only seven steps! Yields may vary. Not peer-reviewed. May cause unexpected death if performed wrong or at all. :D

zed - 21-3-2021 at 13:44

Ummm. Maybe find an acetylating agent with a big fat ass, that will have trouble "getting to" that more sterically "impaired" amino group down South. Use that acetylating agent, to protect your OH, and your Northern NH.

Dehydrogenate your Southern Amino function to a keto-imine. Either hydrolyse to a ketone, or displace the imine via hydroxylamine... Forming an Oxime... Etc. Reduce to desired amine.

Remove your protecting groups.

That being said. I don't like it.

2,6-Dimethoxy-Benzoyl-Chloride? Dunno. Something bulky. Not my field of expertise.

Also of concern. Lotsa centers of asymmetry.

[Edited on 21-3-2021 by zed]

Triflic Acid - 27-3-2021 at 12:50

Maybe you could kill both the secondary amines to primary amines, and use a bulky methylating agent to just remethylate get the amine up north. As a side note, maybe there is a subtle difference in the reactions of an amine directly attached to a ring than an amine attached to a carbon chain? Possibly exploiting that could give something.